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The Shepherds' Tale: A Genome-Wide Study across 9 Dog Breeds Implicates Two Loci in the Regulation of Fructosamine Serum Concentration in Belgian Shepherds.

Forsberg SK, Kierczak M, Ljungvall I, Merveille AC, Gouni V, Wiberg M, Lundgren Willesen J, Hanås S, Lequarré AS, Mejer Sørensen L, Tiret L, McEntee K, Seppälä E, Koch J, Battaille G, Lohi H, Fredholm M, Chetboul V, Häggström J, Carlborg Ö, Lindblad-Toh K, Höglund K - PLoS ONE (2015)

Bottom Line: Considering all breeds together, we did not find any genome-wide significant associations to fructosamine serum concentration.To further explore the genetics of this breed specificity, we screened the genome for reduced heterozygosity stretches private to the Belgian shepherd breed.This revealed a region with reduced heterozygosity that shows a statistically significant interaction (p = 0.025) with the association region on chromosome 3.

View Article: PubMed Central - PubMed

Affiliation: Computational Genetics Section, Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden.

ABSTRACT
Diabetes mellitus is a serious health problem in both dogs and humans. Certain dog breeds show high prevalence of the disease, whereas other breeds are at low risk. Fructosamine and glycated haemoglobin (HbA1c) are two major biomarkers of glycaemia, where serum concentrations reflect glucose turnover over the past few weeks to months. In this study, we searched for genetic factors influencing variation in serum fructosamine concentration in healthy dogs using data from nine dog breeds. Considering all breeds together, we did not find any genome-wide significant associations to fructosamine serum concentration. However, by performing breed-specific analyses we revealed an association on chromosome 3 (pcorrected ≈ 1:68 × 10-6) in Belgian shepherd dogs of the Malinois subtype. The associated region and its close neighbourhood harbours interesting candidate genes such as LETM1 and GAPDH that are important in glucose metabolism and have previously been implicated in the aetiology of diabetes mellitus. To further explore the genetics of this breed specificity, we screened the genome for reduced heterozygosity stretches private to the Belgian shepherd breed. This revealed a region with reduced heterozygosity that shows a statistically significant interaction (p = 0.025) with the association region on chromosome 3. This region also harbours some interesting candidate genes and regulatory regions but the exact mechanisms underlying the interaction are still unknown. Nevertheless, this finding provides a plausible explanation for breed-specific genetic effects for complex traits in dogs. Shepherd breeds are at low risk of developing diabetes mellitus. The findings in Belgian shepherds could be connected to a protective mechanism against the disease. Further insight into the regulation of glucose metabolism could improve diagnostic and therapeutic methods for diabetes mellitus.

No MeSH data available.


Related in: MedlinePlus

A reduced heterozygosity region on CFA5 specific to Belgian shepherds, German shepherds and Boxers.In panel (A), −log10(p−value) of the difference in reference allele count between Belgian shepherds, German shepherds and, Boxers vs. remaining breeds is presented. The three lines in the top panel show the FST values for three sets of comparisons: BS vs. all the remaining breeds (blue), pooled BS and GS vs. all the remaining breeds (red) as well as for pooled BS, GS and BOX vs. all the remaining breeds (black). The FST is averaged in a sliding window of 21 SNPs. The middle panel shows the allele frequencies per SNP for BS, GS, BOX (green) and the other breeds (blue). Panel (B) provides a detailed view on the most significantly differentiated region. Genes compiled from UCSC canine annotation, Broad Improved Canine Annotation v1 [22] and RefSeq [23] human homologue genes are represented by blue rectangles. Arrows show transcription direction. All annotation units likely to be pseudogenes were removed with the exception of AFG3L1P which overlaps with the strongest signal in the scan for allele frequency difference. Also conservation across species (human, mouse, rat) is shown. Letters on panel (A) mark loci with the lowest p-value and the same letters are used in panel (B) to denote position of the same markers.
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pone.0123173.g003: A reduced heterozygosity region on CFA5 specific to Belgian shepherds, German shepherds and Boxers.In panel (A), −log10(p−value) of the difference in reference allele count between Belgian shepherds, German shepherds and, Boxers vs. remaining breeds is presented. The three lines in the top panel show the FST values for three sets of comparisons: BS vs. all the remaining breeds (blue), pooled BS and GS vs. all the remaining breeds (red) as well as for pooled BS, GS and BOX vs. all the remaining breeds (black). The FST is averaged in a sliding window of 21 SNPs. The middle panel shows the allele frequencies per SNP for BS, GS, BOX (green) and the other breeds (blue). Panel (B) provides a detailed view on the most significantly differentiated region. Genes compiled from UCSC canine annotation, Broad Improved Canine Annotation v1 [22] and RefSeq [23] human homologue genes are represented by blue rectangles. Arrows show transcription direction. All annotation units likely to be pseudogenes were removed with the exception of AFG3L1P which overlaps with the strongest signal in the scan for allele frequency difference. Also conservation across species (human, mouse, rat) is shown. Letters on panel (A) mark loci with the lowest p-value and the same letters are used in panel (B) to denote position of the same markers.

Mentions: To search for potential genetic determinants of the observed breed specificity, we performed an across-breed scan for extreme differences in allele frequency to identify regions where the BS breed alone shows reduced heterozygosity. Our working hypothesis was that such regions might contain alleles that modulate the effect of the FructoCFA3 locus through epistatic interactions. For every SNP, we calculated the absolute difference in an arbitrarily chosen reference allele frequency between BS and the remaining studied breeds fdiff = ∣fBS−fremainingbreeds∣, where fBS and fotherbreeds are the allele frequencies in the BS breed and the remaining breeds respectively. Using this method, we identified a locus on chromosome 5 (CFA5, Table 2, S9 Fig) that is close to fixation for one allele in BS. Upon closer examination, we found the identified locus to be close to fixation in BS, German shepherds and Boxers (fBS, GS, BOX = 0.022, allele = G) (Fig 3), and almost fixed for the other allele in the remaining breeds (fotherbreeds = 0.92, allele = A). We also performed additional analyses of the entire CFA5 comparing fixation index (FST) between different subsets of BS, GS and BOX vs. the remaining breeds. The fixation index analyses results (Fig 3, S10 Fig) provide further evidence for the existence of a BS, GS and BOX-specific reduced heterozygosity region and also indicates that the observed pattern might be the signature of historical selection on this region. The detected region of reduced heterozygosity harbours several genes (including human RefSeq genes): kinesin family member 1B (KIF1B), meiosis-specific nuclear structural 1 (MNS1), PR domain containing 7 (PRDM7), urate (hydroxyiso-) hydrolase pseudogene (URAHP), growth arrest-specific 8 (GAS8), dysbindin domain containing 1 (DBNDD1), AFG3-like AAA ATPase 1 pseudogene (AFG3L1P), CENPB DNA-binding domains containing 1 (CENPBD1), differentially expressed in FDCP 8 homolog (DEF8), tubulin, beta 3 class III (TUBB3), melanocortin 1 receptor (MC1R), transcription factor 25 (TCF25), spire-type actin nucleation factor 2 (SPIRE2), Fanconi anemia, complementation group A (FANCA), 3-hydroxyisobutyrate dehydrogenase (HIBADH), zinc finger protein 276 (ZNF276), VPS9 domain containing 1 (VPS9D1), spermatogenesis associated 2-like (SPATA2L), cyclin-dependent kinase 10 (CDK10), spermatogenesis associated 33 (SPATA33), charged multivesicular body protein 1A (CHMP1A), renal dipeptidase 1 (DPEP1), copine VII (CPNE7) and spastic paraplegia 7 (SPG7).


The Shepherds' Tale: A Genome-Wide Study across 9 Dog Breeds Implicates Two Loci in the Regulation of Fructosamine Serum Concentration in Belgian Shepherds.

Forsberg SK, Kierczak M, Ljungvall I, Merveille AC, Gouni V, Wiberg M, Lundgren Willesen J, Hanås S, Lequarré AS, Mejer Sørensen L, Tiret L, McEntee K, Seppälä E, Koch J, Battaille G, Lohi H, Fredholm M, Chetboul V, Häggström J, Carlborg Ö, Lindblad-Toh K, Höglund K - PLoS ONE (2015)

A reduced heterozygosity region on CFA5 specific to Belgian shepherds, German shepherds and Boxers.In panel (A), −log10(p−value) of the difference in reference allele count between Belgian shepherds, German shepherds and, Boxers vs. remaining breeds is presented. The three lines in the top panel show the FST values for three sets of comparisons: BS vs. all the remaining breeds (blue), pooled BS and GS vs. all the remaining breeds (red) as well as for pooled BS, GS and BOX vs. all the remaining breeds (black). The FST is averaged in a sliding window of 21 SNPs. The middle panel shows the allele frequencies per SNP for BS, GS, BOX (green) and the other breeds (blue). Panel (B) provides a detailed view on the most significantly differentiated region. Genes compiled from UCSC canine annotation, Broad Improved Canine Annotation v1 [22] and RefSeq [23] human homologue genes are represented by blue rectangles. Arrows show transcription direction. All annotation units likely to be pseudogenes were removed with the exception of AFG3L1P which overlaps with the strongest signal in the scan for allele frequency difference. Also conservation across species (human, mouse, rat) is shown. Letters on panel (A) mark loci with the lowest p-value and the same letters are used in panel (B) to denote position of the same markers.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4430432&req=5

pone.0123173.g003: A reduced heterozygosity region on CFA5 specific to Belgian shepherds, German shepherds and Boxers.In panel (A), −log10(p−value) of the difference in reference allele count between Belgian shepherds, German shepherds and, Boxers vs. remaining breeds is presented. The three lines in the top panel show the FST values for three sets of comparisons: BS vs. all the remaining breeds (blue), pooled BS and GS vs. all the remaining breeds (red) as well as for pooled BS, GS and BOX vs. all the remaining breeds (black). The FST is averaged in a sliding window of 21 SNPs. The middle panel shows the allele frequencies per SNP for BS, GS, BOX (green) and the other breeds (blue). Panel (B) provides a detailed view on the most significantly differentiated region. Genes compiled from UCSC canine annotation, Broad Improved Canine Annotation v1 [22] and RefSeq [23] human homologue genes are represented by blue rectangles. Arrows show transcription direction. All annotation units likely to be pseudogenes were removed with the exception of AFG3L1P which overlaps with the strongest signal in the scan for allele frequency difference. Also conservation across species (human, mouse, rat) is shown. Letters on panel (A) mark loci with the lowest p-value and the same letters are used in panel (B) to denote position of the same markers.
Mentions: To search for potential genetic determinants of the observed breed specificity, we performed an across-breed scan for extreme differences in allele frequency to identify regions where the BS breed alone shows reduced heterozygosity. Our working hypothesis was that such regions might contain alleles that modulate the effect of the FructoCFA3 locus through epistatic interactions. For every SNP, we calculated the absolute difference in an arbitrarily chosen reference allele frequency between BS and the remaining studied breeds fdiff = ∣fBS−fremainingbreeds∣, where fBS and fotherbreeds are the allele frequencies in the BS breed and the remaining breeds respectively. Using this method, we identified a locus on chromosome 5 (CFA5, Table 2, S9 Fig) that is close to fixation for one allele in BS. Upon closer examination, we found the identified locus to be close to fixation in BS, German shepherds and Boxers (fBS, GS, BOX = 0.022, allele = G) (Fig 3), and almost fixed for the other allele in the remaining breeds (fotherbreeds = 0.92, allele = A). We also performed additional analyses of the entire CFA5 comparing fixation index (FST) between different subsets of BS, GS and BOX vs. the remaining breeds. The fixation index analyses results (Fig 3, S10 Fig) provide further evidence for the existence of a BS, GS and BOX-specific reduced heterozygosity region and also indicates that the observed pattern might be the signature of historical selection on this region. The detected region of reduced heterozygosity harbours several genes (including human RefSeq genes): kinesin family member 1B (KIF1B), meiosis-specific nuclear structural 1 (MNS1), PR domain containing 7 (PRDM7), urate (hydroxyiso-) hydrolase pseudogene (URAHP), growth arrest-specific 8 (GAS8), dysbindin domain containing 1 (DBNDD1), AFG3-like AAA ATPase 1 pseudogene (AFG3L1P), CENPB DNA-binding domains containing 1 (CENPBD1), differentially expressed in FDCP 8 homolog (DEF8), tubulin, beta 3 class III (TUBB3), melanocortin 1 receptor (MC1R), transcription factor 25 (TCF25), spire-type actin nucleation factor 2 (SPIRE2), Fanconi anemia, complementation group A (FANCA), 3-hydroxyisobutyrate dehydrogenase (HIBADH), zinc finger protein 276 (ZNF276), VPS9 domain containing 1 (VPS9D1), spermatogenesis associated 2-like (SPATA2L), cyclin-dependent kinase 10 (CDK10), spermatogenesis associated 33 (SPATA33), charged multivesicular body protein 1A (CHMP1A), renal dipeptidase 1 (DPEP1), copine VII (CPNE7) and spastic paraplegia 7 (SPG7).

Bottom Line: Considering all breeds together, we did not find any genome-wide significant associations to fructosamine serum concentration.To further explore the genetics of this breed specificity, we screened the genome for reduced heterozygosity stretches private to the Belgian shepherd breed.This revealed a region with reduced heterozygosity that shows a statistically significant interaction (p = 0.025) with the association region on chromosome 3.

View Article: PubMed Central - PubMed

Affiliation: Computational Genetics Section, Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden.

ABSTRACT
Diabetes mellitus is a serious health problem in both dogs and humans. Certain dog breeds show high prevalence of the disease, whereas other breeds are at low risk. Fructosamine and glycated haemoglobin (HbA1c) are two major biomarkers of glycaemia, where serum concentrations reflect glucose turnover over the past few weeks to months. In this study, we searched for genetic factors influencing variation in serum fructosamine concentration in healthy dogs using data from nine dog breeds. Considering all breeds together, we did not find any genome-wide significant associations to fructosamine serum concentration. However, by performing breed-specific analyses we revealed an association on chromosome 3 (pcorrected ≈ 1:68 × 10-6) in Belgian shepherd dogs of the Malinois subtype. The associated region and its close neighbourhood harbours interesting candidate genes such as LETM1 and GAPDH that are important in glucose metabolism and have previously been implicated in the aetiology of diabetes mellitus. To further explore the genetics of this breed specificity, we screened the genome for reduced heterozygosity stretches private to the Belgian shepherd breed. This revealed a region with reduced heterozygosity that shows a statistically significant interaction (p = 0.025) with the association region on chromosome 3. This region also harbours some interesting candidate genes and regulatory regions but the exact mechanisms underlying the interaction are still unknown. Nevertheless, this finding provides a plausible explanation for breed-specific genetic effects for complex traits in dogs. Shepherd breeds are at low risk of developing diabetes mellitus. The findings in Belgian shepherds could be connected to a protective mechanism against the disease. Further insight into the regulation of glucose metabolism could improve diagnostic and therapeutic methods for diabetes mellitus.

No MeSH data available.


Related in: MedlinePlus